Epilepsy is a leading neurological disorder, second only to stroke. One to four million Americans and twenty to forty million people world-wide suffer from some form of epilepsy, making it second only to stroke as the leading neurological disorder. Although standard therapy permits control of seizures in 80% of these patients, one-half million people in the U.S. have uncontrolled epilepsy. The number of drugs useful for the treatment of epilepsy is remarkably small. Fewer than 20 drugs are currently marketed in the U.S., and of these, only five or six are widely used. Complex partial epilepsy (also known as temporal lobe, psycomotor or limbic epilepsy), the most devastating form among adults, and estimated to account for an many as two-thirds of all cases, is refractory to drug treatment (Gummit, R. J., "The Epilepsy Handbook, The Practical Management of Seizures", Raven Press, New York, 1983). It is becoming increasingly evident that significant progress toward complete control can be achieved only by an understanding of the mechanisms of the epilepsies themselves, which will provide the molecular basis for antiepileptic drug design and development, and new treatment strategies. Out of the twenty or so new drugs that are in clinical trial in the U.S., only a few have been developed based on the knowledge of epilepsy mechanisms (Dichter, M. A., Epilepsia, 30, S3-S12, 1989).
NMDA receptor overstimulation by high levels of the excitatory amino acid (EAA), L-glutamate, has been implicated in epileptogenesis and epilepsy (Cavalheiro, et al., "Frontiers in Excitatory Amino Acid Research", A. R. Liss, New York, 1988). Thus, development of agents that are EAA/NMDA antagonists may constitute novel and effective therapies for the epilepsies. Although a number of excitatory amino acid (EAA) inhibitors have been discovered, many lack NMDA receptor specificity and are too toxic for clinical studies (Porter, Epilepsia, 30, S29-34, 1989). Thus, the discovery of this invention of certain aminoalkylpyridines as a superior class of anticonvulsant agents in the Applicant's laboratories is significant. The aminoalkylpyridines of this invention are potent, orally active, nonneurotoxic NMDA antagonists that hold promise for commercial development as nontoxic, clinically useful antiepileptic drugs. They can provide the basis for the design of safer NMDA antagonists with increased potency and reduced toxicity for the management of epilepsy in humans.
Certain aminoalkylpyridines are known to the art as described in U.S. Pat. Nos. 4,358,446, 3,522,262, and 3,654,290. Aminoalkyl-3-pyridines are described in U.S. Pat. No. 4,358,446 as intermediates in the preparation of certain N-acylaminoalkyl-3-pyridine derivatives that have activity as fungicides. U.S. Pat. Nos. 3,522,262 and 3,654,290, describe aminoalkylpyridines as intermediates for preparation of certain indole derivatives which have antiallergic activity.